rs528255772

Positions:

• chr5-128392078-A-G
• chr5-128392078-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001999.4(FBN2):​c.1543T>C​(p.Ser515Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S515T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FBN2 NM_001999.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.25

Genes affected

FBN2 (HGNC:3604): (fibrillin 2) The protein encoded by this gene is a component of connective tissue microfibrils and may be involved in elastic fiber assembly. Mutations in this gene cause congenital contractural arachnodactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, FBN2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FBN2	NM_001999.4	c.1543T>C	p.Ser515Pro	missense_variant	11/65	ENST00000262464.9
FBN2	XM_017009228.3	c.1390T>C	p.Ser464Pro	missense_variant	10/64

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FBN2	ENST00000262464.9	c.1543T>C	p.Ser515Pro	missense_variant	11/65	1	NM_001999.4	P1
FBN2	ENST00000508989.5	c.1444T>C	p.Ser482Pro	missense_variant	10/33	2
FBN2	ENST00000703787.1	n.1250T>C		non_coding_transcript_exon_variant	10/10

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;D;D
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.57	T;.;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.2	L;.;L;.
MutationTaster	Benign	0.98	N;N;N
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.9	D;.;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.015	D;.;D;D
Polyphen		0.81	P;.;P;D
Vest4		0.71
MutPred		0.64		Gain of glycosylation at T513 (P = 0.1341);.;Gain of glycosylation at T513 (P = 0.1341);.;
MVP		0.80
MPC		0.80
ClinPred		0.98	D
GERP RS		4.1
Varity_R		0.45
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-127727771; COSMIC: COSV52535464;